This study attempts to manipulate bone cell lysosomal activity in vivo and to determine the influence of phosphatase activity in skeletal growth and remodeling. Techniques used involve quantitation of acid, alkaline and neutral phosphatase in fresh metaphyseal bone, histochemistry of the same enzyme activity and electron microscopic investigation of morphological changes. To date we have observed the following: 1. Diphosphonate, given in subcutaneous doses too small to inhibit growth in rats, will reduce bone cell lysosomal activity. 2. Orally administered diphosphonate has less effect on skeletal acid phosphatase than the injected doses, however it tends to raise the alkaline phosphatase content in the skeleton. 3. Injected estrogens will depress both acid and alkaline phosphatase but tends to have more effect on acid phosphatase in males and alkaline phosphatase in females. 4. The ia rat strain has osteoclasts which respond very poorly to exogenously administered parathyroid hormone however the serum calcium is always maintained within normal limits. Osteoclastic response to parathyroid hormone is measured in terms of an increase in lysosomal phosphatase activity which when measured at a neutral pH is highly specific for bone cells. 5. Chloroquine can inhibit lysosomal degradation of mucopolysaccharides in cultured human fibroblasts. By increasing the pH of the culture media, even without addition of chloroquine, an inhibition of lysosomal activity is seen. These results are similarly found in several mucopolysaccharide disorders. Further studies will investigate the interaction of estrogen and progesterone on skeletal enzyme activity and the influence of these compounds on parathyroid hormone response in the skeleton.